Erythroliposomes: Integrated Hybrid Nanovesicles Composed of Erythrocyte Membranes and Artificial Lipid Membranes for Pore-Forming Toxin Clearance

Pore-forming toxins (PFTs) are the most common bacterial virulence proteins and play a significant role in the pathogenesis of bacterial infections; thus, PFTs are an attractive therapeutic target in bacterial infections. Inspired by the pore-forming process and mechanism of PFTs, we designed an integrated hybrid nanovesiclethe erythroliposome (called the RM-PL)for PFT detoxification by fusing natural red blood cell (RBC) membranes with artificial lipid membranes. The lipid and RBC membranes were mutually beneficial when integrated into a hybrid nanovesicle structure. The RBC membrane endowed RM-PLs with the capacity for detoxification, while the PEGylated lipid membrane stabilized the RM-PLs and greatly improved the detoxification capacity of the RBC membrane. With α-hemolysin (Hlα) as a model PFT, we demonstrated that RM-PLs could not only significantly reduce the toxicity of Hlα to erythrocytes in vitro but also effectively sponge Hlα in vivo and rescue mice from Hlα-induced damage. Moreover, the high detoxification capacity of RM-PLs was shown to be partly related to the expression of the Hlα receptor protein, a disintegrin and metalloproteinase domain-containing protein 10 on the RBC membrane. Consequently, as a component integrating natural and artificial materials, the erythroliposome nanoplatform inspires potential strategies for antivirulence therapy.

穿孔素（Pore-forming toxins，PFTs）是最常见的细菌毒力蛋白，在细菌感染的致病过程中发挥关键作用，因此PFTs是细菌感染治疗中极具吸引力的治疗靶点。受PFTs的成孔过程与作用机制启发，我们将天然红细胞（RBC）膜与人工脂质膜融合，设计出一种集成杂合纳米囊泡——红细胞脂质体（erythroliposome，简称RM-PL），用于PFT的解毒治疗。该杂合纳米囊泡结构中，脂质膜与RBC膜实现了互利共赢：RBC膜赋予RM-PL基础解毒能力，而聚乙二醇化脂质膜则稳定了RM-PL，并大幅提升了RBC膜的整体解毒效能。以α-溶血素（α-hemolysin，Hlα）作为模型PFT，我们证实RM-PL不仅可在体外显著降低Hlα对红细胞的毒性，还能在体内有效捕获并清除Hlα，使小鼠免于Hlα诱导的机体损伤。进一步研究表明，RM-PL的高解毒能力部分与RBC膜上Hlα的受体蛋白——解整合素和金属蛋白酶结构域包含蛋白10的表达相关。综上，作为整合天然与人工材料的纳米平台，该红细胞脂质体为抗毒力治疗提供了极具潜力的全新策略。